Autoimmunity has long been associated with pulmonary hypertension (PH) but has not been systematically examined as a root cause for this frequently fatal condition. Connective tissue disease and viral infections are systemic disorders that are strongly linked with PH and are characterized by or have a propensity to autoimmunity. Using an experimental model of vascular endothelial growth factor receptor (VEGFR) blockade-induced PH, it is evident that autoimmune injury may actually initiate this disease. It has been previously demonstrated that VEGFR blockade leads to pulmonary vascular endothelial cell apoptosis and that if animals are exposed to hypoxemia, PH will ensue. However, this experimental model, as with most experimental models, can not recreate the clinical evolution of PH which occurs in patients living in normoxic environments. Preliminary findings demonstrate that severe PH will develop following VEGFR blockade in Denver altitude conditions if administered to experimental animals that lack T cells (i.e. the athymic nude rat) but not if lymphocytes are restored to these animals. These seminal observations have formed the basis for this revised R01 proposal. The overarching hypothesis for this project is that there is an autoimmune basis for the development of PH. This autoimmunity may be the result of a lack of appropriate regulatory T cell activity. Specific Aim I will determine whether CD4 or CDS cell populations are responsible for preventing PH in athymic rats treated with VEGFR blockade and test the general hypothesis that T cell subsets are sufficient to prevent VEGFR blockade-induced PH in athymic rats. An additional component of this Aim will be to demonstrate that protection from PH correlates with prevention of anti-endothelial antibody formation. Specific Aim II will be to determine whether spleen cell protection of VEGFR blockade-induced PH in athymic rats is time-dependent to test the hypothesis that PH may be prevented during a putative initiation phase but becomes irreversible during a progressive phase. Specific Aim III will be to determine whether PH can be induced in euthymic rats with CD4 depletion and will test the hypothesis that acquired immunodeficiency in wild type rats is sufficient to render these animals susceptible to VEGFR blockade-induced PH. If it can be determined that PH has its roots in autoimmune events, rational therapeutic design can better consider early disease pathogenesis in this frequently lethal condition.